Medical devices having adherent polymeric layers with depth-dependent properties

ABSTRACT

According to one aspect of the invention, a method of forming a medical device is provided, which includes: (a) contacting a substrate with a solution that contains (i) one or more types of polymers, (ii) a solvent that contains one or more types of solvent species, and (iii) one or more optional agents, for example, one or more therapeutic agents, among others; and (b) removing the solvent from the solution, thereby forming a polymeric layer on the substrate. The composition of the solution is changed over the course of forming the polymeric layer. In another aspect of the invention, a medical device is provided, which includes a substrate and a polymeric layer over the substrate. The polymeric layer contains a copolymer that contains differing first and second monomers. The lower surface of the polymeric layer contacting the substrate has a surface concentration of the first monomer relative to the second monomer that is higher than that of the upper surface of the polymeric layer opposite the substrate.

STATEMENT OF RELATED APPLICATION

This application claims the benefit of U.S. patent application Ser. No.11/983,952 filed Nov. 13, 2007, and U.S. Provisional Patent ApplicationSer. No. 60/858,634, filed Nov. 13, 2006, all of which are incorporatedby reference herein.

FIELD OF THE INVENTION

The present invention relates generally to medical devices, and moreparticularly to implantable or insertable medical devices which containadherent polymeric layers.

BACKGROUND OF THE INVENTION

Numerous polymer-based medical devices have been developed forimplantation or insertion into the body. For example, various state ofthe art medical devices consist of a medical device substrate with apolymeric coating that serves as a reservoir for one or more therapeuticagents. Specific examples include drug eluting coronary stents,commercially available from Boston Scientific Corp. (TAXUS), Johnson &Johnson (CYPHER) and others, which have become the standard of care formaintaining vessel patency after balloon angioplasty. These products arebased on metallic balloon expandable stents with polymeric coatings thatrelease antiproliferative drugs at a controlled rate and total doseeffective to inhibit the smooth muscle proliferation that is associatedwith restenosis (vessel reclosure).

Various types of polymeric materials have been used as drug-releasingreservoirs, including, for example, homopolymers such as poly(n-butylmethacrylate) and copolymers such as poly(isobutylene-co-styrene), forexample, poly(styrene-b-isobutylene-b-styrene) triblock copolymers(SIBS), which are described, for instance, in U.S. Pat. No. 6,545,097 toPinchuk et al. In addition to their utility as drug delivery reservoirs,SIBS copolymers have proven valuable for a variety of reasons, includingtheir excellent biocompatibility, elasticity, strength, andprocessability. The latter characteristics are due, at least in part, tothe fact that SIBS copolymers are thermoplastic elastomers.Thermoplastic elastomers are elastomeric (i.e., reversibly deformable)polymers that form physical crosslinks which can be reversed, forexample, by dissolving or melting the polymer. SIBS triblock copolymershave an elastomeric low glass transition temperature (Tg) midblock andhard elevated Tg endblocks. As with many block copolymers, SIBS tends tophase separate, with the elastomeric blocks aggregating to formelastomeric phase domains and the hard blocks aggregating to form hardphase domains. It has been hypothesized that, because each elastomericblock has a hard block at each end, and because different hard blockswithin the same triblock copolymer are capable of occupying twodifferent hard phase domains, the hard phase domains become physicallycrosslinked to one another via the soft blocks.

SUMMARY OF THE INVENTION

According to an aspect of the invention, a method of forming a medicaldevice is provided, which includes: (a) contacting a substrate with asolution that contains (i) one or more types of polymers, (ii) a solventthat contains one or more types of solvent species, and (iii) one ormore optional agents, for example, one or more therapeutic agents, amongothers; and (b) removing the solvent from the solution, thereby forminga polymeric layer on the substrate. In the method of the presentinvention, the composition of the solution is changed over the course offorming the polymeric layer.

According to another aspect of the invention, a medical device isprovided, which includes a substrate and a polymeric layer over thesubstrate. The polymeric layer contains a copolymer that in turncontains differing first and second monomers, which may, for example,form first and second polymer blocks, as discussed further below. Thelower surface of the polymeric layer contacting the substrate has asurface concentration of the first monomer relative to the secondmonomer that is higher than that of the upper surface of the polymericlayer opposite the substrate.

These and other aspects and embodiments of the present invention, aswell as various advantages, will become immediately apparent to those ofordinary skill in the art upon review of the Detailed Description andClaims to follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic perspective view of a stent in accordance withthe prior art.

FIG. 1B is a schematic cross-sectional view of the stent of FIG. 1,taken along line b-b.

FIG. 2A is a schematic cross-sectional view like that of FIG. 1B, inaccordance with an embodiment of the invention.

FIG. 2B is a schematic cross-sectional view like that of FIG. 1B, inaccordance with another embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

According to an aspect of the invention, a method of forming a medicaldevice is provided, which includes: (a) contacting a substrate with asolution that contains (i) one or more types of polymers, (ii) a solventthat contains one or more types of solvent species, and (iii) one ormore optional agents, for example, one or more therapeutic agents, amongothers; and (b) removing the solvent from the solution, thereby forminga polymeric layer on the substrate. The composition of the solution ischanged over the course of forming the polymeric layer, changing theproperties of the same.

Preferably, at the beginning of the layer formation process, thecomposition of the solution is selected to optimize adhesion between thepolymeric layer and the substrate, whereas the composition of thesolution is subsequently modified in order to provide the layer withanother beneficial property, for example, effective drug releasecharacteristics, lower surface tack, and/or an optimized interface,among many others. Generally, the initial solution composition providesgreater substrate adhesion than the subsequent solution composition(s).

Such a method may be used, for example, to apply a polymeric layer to acoronary stent substrate, among many other medical device substrates,such as those described below. In this regard, in a current process forforming TAXUS products, the outer surface of a stainless steel coronarystent is sprayed with a solution that contains solvent, paclitaxel andSIBS. Although the solution is spayed on the outside of the stent, thestent is ultimately encapsulated with the polymeric coating due towicking of the solution around the stent struts. The result of such aprocess is schematically illustrated, for example, in FIGS. 1A and 1B.FIG. 1A shows a stent 100 which contains a number of interconnectedstruts 100 s. FIG. 1B is a cross-section taken along line b-b of strut110 s of stent 100 of FIG. 1A, and shows a stainless steel stentsubstrate 110 and a paclitaxel-containing polymeric coating 120, whichencapsulates the substrate 110. Typical thicknesses along the exterior(abluminal) surface 110 a range from 1 to 50 μm, more typically 15 to 25μm, whereas typical thicknesses along the interior (luminal) surface1101 also range from 1 to 50 μm, more typically 7 to 15 μm. Thesolution, which contains paclitaxel, SIBS (16 mol % styrene, 84 mol %isobutylene), and a solvent that consists of 95 vol % toluene and 5 vol% tetrahydrofuran, yields a polymeric layer with a weight ratio ofpolymer to drug about 10 to 1, and provides a kinetic drug release (KDR)that is safe and effective for the treatment of restenosis. The coatinghas relatively poor adhesion to the stent substrate surface, but isnonetheless well-secured to the stent substrate as a result of theencapsulation that occurs (and the inherent strength of SIBS).

While it is desirable to provide the abluminal surface of the stent witha polymeric coating that is capable of releasing an antiproliferativedrug to combat restenosis, such a drug may not be equally desirable onthe luminal surface of the stent and, in fact, may even be detrimentalto the extent that it may retard or interfere with the growth of healthyendothelial cells on the luminal surface of the stent. Moreover, thepresence of a polymeric layer on the luminal surface is not needed forpurposes of promoting biocompatibility, as various stent substratematerials, including stainless steel, are known to support endothelialcell growth. An embodiment of the invention in which apaclitaxel-containing polymeric layer 120 is applied to only theabluminal surface 110 a of the stent substrate 110 is illustrated in thestrut cross section of FIG. 2A. Another embodiment is illustrated inFIG. 2B, wherein a paclitaxel-containing polymeric layer 120 is appliedto the abluminal surface 110 a of the stent substrate 110 and on theadjacent edges as well. Such layers 120 may be created, for example, bymasking the inner surface of the stent 100 during deposition of thepolymer layer, by removing polymeric material from the luminal surfaceof the stent after creating the polymeric layer 120, by coating atubular stent precursor with the polymeric layer 120 prior to removingmaterial (e.g., by cutting, punching, etc.) to form the apertures (andthus the struts) of the stent, or by any other suitable methodology.

If such a polymeric layer were to be applied to the stent using thecoating solution described above, the polymeric layer could exhibitaltered adhesion properties between the stent and the polymeric layer.If the solution composition were to be changed to improve adhesion, thedrug release characteristic of the coating, among other properties,could be altered, which may or may not be desirable.

The devices and methods of the present invention address such tradeoffsin properties, among others.

As noted above, methods in accordance with the present invention relyupon a change in solution composition over the course of polymeric layerformation.

For example, at the beginning of the layer formation process, thecomposition of the solvent may be selected to provide sufficientadhesion of the polymeric layer to the substrate, with the compositionof the solvent subsequently being modified in order to provide the layerwith another beneficial property, for example, reduced surface tackand/or a drug release profile that has proven to be safe and effectivefor the treatment of a disease or condition, among others.

As used herein, “treatment” refers to the prevention of a disease orcondition, the reduction or elimination of symptoms associated with adisease or condition, or the substantial or complete elimination of adisease or condition. Preferred subjects (also referred to as“patients”) are vertebrate subjects, more preferably mammalian subjectsand more preferably human subjects.

As used herein a “layer” of a given material is a region of thatmaterial whose thickness is small compared to both its length and width.Terms such as “film,” “layer” and “coating” may be used interchangeablyherein. As used herein a layer need not be planar, for example, takingon the contours of an underlying substrate. Layers can be discontinuous(e.g., patterned).

As used herein a “polymeric layer” is a layer that contains one or moretypes of polymers, typically containing 50 wt % to 75 wt % to 90 wt % to95 wt % to 97.5 wt % to 99 wt % polymers, or even more, among otherranges.

Coating thickness may vary widely, for example, ranging from 1 to 2.5 to5 to 10 to 25 to 50 to 100 μm, with 5 to 30 μm being typical for stentapplications among others.

In polymeric layers produced in accordance with the present inventionwhere drug is present, drug may or may not be present throughout thelayer. In an example of the latter case, drug may be present throughoutthe layer, except in the region of the layer that is adjacent to thepolymer-substrate interface (e.g., in instances where the drug mayinterfere with adhesion, etc.).

A wide range of therapeutic agent loadings can be used in conjunctionwith the polymeric layers of the present invention, with thetherapeutically effective concentration and amount being readilydetermined by those of ordinary skill in the art and ultimatelydepending, for example, upon the condition to be treated, the age, sexand condition of the subject, the nature of the therapeutic agent, thenature of the polymeric layer, and the nature of the medical device,among other factors. The amount of therapeutic agent commonly rangesfrom 0.1 to 30 wt %, among other ranges.

As used herein, “polymers” are molecules containing multiple copies(e.g., 5 to 10 to 25 to 50 to 100 to 250 to 500 to 1000 or more copies)of one or more constitutional units, commonly referred to as monomers.Polymers may take on a number of configurations, which may be selected,for example, from cyclic, linear, branched and networked (e.g.,crosslinked) configurations. Branched configurations include star-shapedconfigurations (e.g., configurations in which three or more chainsemanate from a single branch point, such as a seed molecule), combconfigurations (e.g., configurations having a main chain and a pluralityof side chains), dendritic configurations (e.g., arborescent andhyperbranched polymers), and so forth.

As used herein, “homopolymers” are polymers that contain multiple copiesof a single constitutional unit. “Copolymers” are polymers that containmultiple copies of at least two dissimilar constitutional units,examples of which include random, statistical, gradient, periodic (e.g.,alternating) and block copolymers. As used herein, “block copolymers”are copolymers that contain two or more differing polymer blocks, forinstance, because a constitutional unit (i.e., a monomer) is found inone polymer block that is not found in another polymer block. As usedherein, a “polymer block” is a grouping of constitutional units (e.g., 5to 10 to 25 to 50 to 100 to 250 to 500 to 1000 or more units). Blockscan be branched or unbranched. Blocks can contain a single type ofconstitutional unit (“homopolymeric blocks”) or multiple types ofconstitutional units (“copolymeric blocks”) which may be provided, forexample, in a random, statistical, gradient, or periodic (e.g.,alternating) distribution.

A few examples of block copolymer structures include the following,among others: (a) block copolymers having alternating blocks of the type(AB)m, B(AB)m and A(BA)m where A is a polymer block (e.g., a polystyreneblock), B is a different polymer block (e.g., a polyisobutylene block),m is a positive whole number of 1 or more, and (b) block copolymershaving multi-arm geometries, such as X(BA)n, and X(AB)n, where n is apositive whole number of 2 or more and X is a hub species (e.g., aninitiator molecule residue, a residue of a molecule to which preformedpolymer chains are attached, etc.). In addition to the hub speciesmentioned above, copolymers such as those above can contain a variety ofother non-polymer-chain species, which are commonly present incopolymers, including capping molecules, among others. Note thatnon-polymer species, such as hub species, linking species, etc. aregenerally ignored in describing block copolymer morphology, for example,with X(BA)2 being designated as an ABA triblock copolymer. Otherexamples of block copolymers include comb copolymers having a B chainbackbone and multiple A side chains, as well as comb copolymers havingan A chain backbone and multiple B side chains.

Specific polymers for forming polymeric layers in accordance with theinvention may be selected, for example, from suitable members of thefollowing and blends thereof: polycarboxylic acid polymers andcopolymers including polyacrylic acids; acetal polymers and copolymers;acrylate and methacrylate polymers and copolymers (e.g., n-butylmethacrylate); cellulosic polymers and copolymers, including celluloseacetates, cellulose nitrates, cellulose propionates, cellulose acetatebutyrates, cellophanes, rayons, rayon triacetates, and cellulose etherssuch as carboxymethyl celluloses and hydroxyalkyl celluloses;polyoxymethylene polymers and copolymers; polyimide polymers andcopolymers such as polyether block imides and polyether block amides,polyamidimides, polyesterimides, and polyetherimides; polysulfonepolymers and copolymers including polyarylsulfones andpolyethersulfones; polyamide polymers and copolymers including nylon6,6, nylon 12, polycaprolactams and polyacrylamides; resins includingalkyd resins, phenolic resins, urea resins, melamine resins, epoxyresins, allyl resins and epoxide resins; polycarbonates;polyacrylonitriles; polyvinylpyrrolidones (cross-linked and otherwise);polymers and copolymers of vinyl monomers including polyvinyl alcohols,polyvinyl halides such as polyvinyl chlorides, ethylene-vinyl acetatecopolymers (EVA), polyvinylidene chlorides, polyvinyl ethers such aspolyvinyl methyl ethers, polystyrenes, styrene-maleic anhydridecopolymers, vinyl-aromatic-olefin copolymers, includingstyrene-butadiene copolymers, styrene-ethylene-butylene copolymers(e.g., a polystyrene-polyethylene/butylene-polystyrene (SEBS) copolymer,available as Kraton® G series polymers), styrene-isoprene copolymers(e.g., polystyrene-polyisoprene-polystyrene), acrylonitrile-styrenecopolymers, acrylonitrile-butadiene-styrene copolymers,styrene-butadiene copolymers and styrene-isobutylene copolymers (e.g.,polyisobutylene-polystyrene and polystyrene-polyisobutylene-polystyreneblock copolymers such as those disclosed in U.S. Pat. No. 6,545,097 toPinchuk), polyvinyl ketones, polyvinylcarbazoles, and polyvinyl esterssuch as polyvinyl acetates; polybenzimidazoles; ethylene-methacrylicacid copolymers and ethylene-acrylic acid copolymers, where some of theacid groups can be neutralized with either zinc or sodium ions (commonlyknown as ionomers); polyalkyl oxide polymers and copolymers includingpolyethylene oxides (PEO); polyesters including polyethyleneterephthalates and aliphatic polyesters such as polymers and copolymersof lactide (which includes lactic acid as well as d-,l- and mesolactide), epsilon-caprolactone, glycolide (including glycolic acid),hydroxybutyrate, hydroxyvalerate, para-dioxanone, trimethylene carbonate(and its alkyl derivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one, and6,6-dimethyl-1,4-dioxan-2-one (a copolymer of poly(lactic acid) andpoly(caprolactone) is one specific example); polyether polymers andcopolymers including polyarylethers such as polyphenylene ethers,polyether ketones, polyether ether ketones; polyphenylene sulfides;polyisocyanates; polyolefin polymers and copolymers, includingpolyalkylenes such as polypropylenes, polyethylenes (low and highdensity, low and high molecular weight), polybutylenes (such aspolybut-1-ene and polyisobutylene), polyolefin elastomers (e.g.,santoprene), ethylene propylene diene monomer (EPDM) rubbers,poly-4-methyl-pen-1-enes, ethylene-alpha-olefin copolymers,ethylene-methyl methacrylate copolymers and ethylene-vinyl acetatecopolymers; fluorinated polymers and copolymers, includingpolytetrafluoroethylenes (PTFE),poly(tetrafluoroethylene-co-hexafluoropropene) (FEP), modifiedethylene-tetrafluoroethylene copolymers (ETFE), and polyvinylidenefluorides (PVDF); silicone polymers and copolymers; thermoplasticpolyurethanes (TPU); elastomers such as elastomeric polyurethanes andpolyurethane copolymers (including block and random copolymers that arepolyether based, polyester based, polycarbonate based, aliphatic based,aromatic based and mixtures thereof; examples of commercially availablepolyurethane copolymers include Bionate®, Carbothane®, Tecoflex®,Tecothane®, Tecophilic®, Tecoplast®, Pellethane®, Chronothane® andChronoflex®); p-xylylene polymers; polyiminocarbonates;copoly(ether-esters) such as polyethylene oxide-polylactic acidcopolymers; polyphosphazines; polyalkylene oxalates; polyoxaamides andpolyoxaesters (including those containing amines and/or amido groups);polyorthoesters; biopolymers, such as polypeptides, proteins,polysaccharides and fatty acids (and esters thereof), including fibrin,fibrinogen, collagen, elastin, chitosan, gelatin, starch,glycosaminoglycans such as hyaluronic acid; as well as copolymers of theabove.

Particular examples of polymers for coronary stents include SIBS, ablend of SIBS and poly(styrene-co-maleic anhydride) (SMA),poly(lactide-co-glycolide) (PLGA), and poly(N,N′-methylenebisacrylamide) (MBAM), among many others.

Materials for use as underlying substrates include polymeric materials,ceramic materials and metallic materials.

Specific examples of ceramic substrate materials may be selected, forexample, from materials containing one or more of the following: metaloxides, including aluminum oxides and transition metal oxides (e.g.,oxides of titanium, zirconium, hafnium, tantalum, molybdenum, tungsten,rhenium, and iridium); silicon; silicon-based ceramics, such as thosecontaining silicon nitrides, silicon carbides and silicon oxides(sometimes referred to as glass ceramics); calcium phosphate ceramics(e.g., hydroxyapatite); carbon and carbon-based, ceramic-like materialssuch as carbon nitrides, among many others.

Specific examples of metallic substrate materials may be selected, forexample, from materials containing one or more of the following: metals(e.g., biostable metals such as gold, platinum, palladium, iridium,osmium, rhodium, titanium, tantalum, tungsten, and ruthenium, andbioresorbable metals such as magnesium) and metal alloys, includingmetal alloys comprising iron and chromium (e.g., stainless steels,including platinum-enriched radiopaque stainless steel), alloyscomprising nickel and titanium (e.g., Nitinol), alloys comprising cobaltand chromium, including alloys that comprise cobalt, chromium and iron(e.g., elgiloy alloys), alloys comprising nickel, cobalt and chromium(e.g., MP 35N), alloys comprising cobalt, chromium, tungsten and nickel(e.g., L605), and alloys comprising nickel and chromium (e.g., inconelalloys).

Specific examples of polymeric substrate materials include those thatcontain one or more suitable polymers selected from those listed above,among others.

Examples of medical devices benefiting from the present inventioninclude implantable or insertable medical devices, for example,catheters (e.g., urological or vascular catheters such as ballooncatheters and various central venous catheters), guide wires, balloons,filters (e.g., vena cava filters and mesh filters for distil protectiondevices), stents (including coronary vascular stents, peripheralvascular stents, cerebral, urethral, ureteral, biliary, tracheal,gastrointestinal and esophageal stents), stent coverings, stent grafts,vascular grafts, abdominal aortic aneurysm (AAA) devices (e.g., AAAstents, AAA grafts), vascular access ports, dialysis ports, embolizationdevices including cerebral aneurysm filler coils (including Guglilmidetachable coils and metal coils), embolic agents, hermetic sealants,septal defect closure devices, myocardial plugs, patches, pacemakers,lead coatings including coatings for pacemaker leads, defibrillationleads, and coils, ventricular assist devices including left ventricularassist hearts and pumps, total artificial hearts, shunts, valvesincluding heart valves and vascular valves, anastomosis clips and rings,cochlear implants, tissue bulking devices, and tissue engineeringscaffolds for cartilage, bone, skin and other in vivo tissueregeneration, sutures, suture anchors, tissue staples and ligating clipsat surgical sites, cannulae, metal wire ligatures, urethral slings,hernia “meshes”, artificial ligaments, orthopedic prosthesis such asbone grafts, bone plates, joint prostheses, orthopedic fixation devicessuch as interference screws in the ankle, knee, and hand areas, tacksfor ligament attachment and meniscal repair, rods and pins for fracturefixation, screws and plates for craniomaxillofacial repair, dentalimplants, or other device that is implanted or inserted into the body.

The medical devices of the present invention thus include, for example,implantable and insertable medical devices that are used for systemictreatment, as well as those that are used for the localized treatment ofany mammalian tissue or organ. Non-limiting examples are tumors; organsincluding the heart, coronary and peripheral vascular system (referredto overall as “the vasculature”), the urogenital system, includingkidneys, bladder, urethra, ureters, prostate, vagina, uterus andovaries, eyes, ears, spine, nervous system, lungs, trachea, esophagus,intestines, stomach, brain, liver and pancreas, skeletal muscle, smoothmuscle, breast, dermal tissue, cartilage, tooth and bone.

As noted above, the medical devices of the present invention alsooptionally contain one or more therapeutic agents. “Therapeutic agents,”“drugs,” “pharmaceutically active agents,” “pharmaceutically activematerials,” and other related terms may be used interchangeably herein.These terms include genetic therapeutic agents, non-genetic therapeuticagents and cells.

Exemplary non-genetic therapeutic agents for use in conjunction with thepresent invention include: (a) anti-thrombotic agents such as heparin,heparin derivatives, urokinase, streptokinase, alteplase, anistreplase,reteplase, tenecteplase and PPack (dextrophenylalanine proline argininechloromethylketone); (b) anti-inflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine andmesalamine; (c) antineoplastic/antiproliferative/anti-miotic agents suchas paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin, angiopeptin, monoclonal antibodiescapable of blocking smooth muscle cell proliferation, and thymidinekinase inhibitors; (d) anesthetic agents such as lidocaine, bupivacaineand ropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promoters; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors(e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;(j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobialagents such as triclosan, cephalosporins, aminoglycosides andnitrofurantoin; (m) cytotoxic agents, cytostatic agents and cellproliferation affectors; (n) vasodilating agents; (o) agents thatinterfere with endogenous vasoactive mechanisms; (p) inhibitors ofleukocyte recruitment, such as monoclonal antibodies; (q) cytokines; (r)hormones; (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein,which is a molecular chaperone or housekeeping protein and is needed forthe stability and function of other client proteins/signal transductionproteins responsible for growth and survival of cells) includinggeldanamycin, (t) alpha receptor antagonist (such as doxazosin,Tamsulosin) and beta receptor agonists (such as dobutamine, salmeterol),beta receptor antagonist (such as atenolol, metaprolol, butoxamine),angiotensin-II receptor antagonists (such as losartan, valsartan,irbesartan, candesartan and telmisartan), and antispasmodic drugs (suchas oxybutynin chloride, flavoxate, tolterodine, hyoscyamine sulfate,diclomine), (u) bARKct inhibitors, (v) phospholamban inhibitors, (w)Serca 2 gene/protein, (x) immune response modifiers includingaminoquizolines, for instance, imidazoquinolines such as resiquimod andimiquimod, and (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV,etc.).

Specific examples of non-genetic therapeutic agents include paclitaxel,(including particulate forms thereof, for instance, protein-boundpaclitaxel particles such as albumin-bound paclitaxel nanoparticles,e.g., ABRAXANE), sirolimus, everolimus, tacrolimus, zotarolimus, Epo D,dexamethasone, estradiol, halofuginone, cilostazole, geldanamycin,ABT-578 (Abbott Laboratories), trapidil, liprostin, Actinomcin D,Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers,bARKct inhibitors, phospholamban inhibitors, Serca 2 gene/protein,imiquimod, human apolioproteins (e.g., AI-AV), growth factors (e.g.,VEGF-2), as well a derivatives of the forgoing, among others.

Exemplary genetic therapeutic agents for use in conjunction with thepresent invention include anti-sense DNA and RNA as well as DNA codingfor the various proteins (as well as the proteins themselves): (a)anti-sense RNA, (b) tRNA or rRNA to replace defective or deficientendogenous molecules, (c) angiogenic and other factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, endothelial mitogenic growth factors,epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor andinsulin-like growth factor, (d) cell cycle inhibitors including CDinhibitors, and (e) thymidine kinase (“TK”) and other agents useful forinterfering with cell proliferation. Also of interest is DNA encodingfor the family of bone morphogenic proteins (“BMP's”), including BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferredBMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. Thesedimeric proteins can be provided as homodimers, heterodimers, orcombinations thereof, alone or together with other molecules.Alternatively, or in addition, molecules capable of inducing an upstreamor downstream effect of a BMP can be provided. Such molecules includeany of the “hedgehog” proteins, or the DNA's encoding them.

Vectors for delivery of genetic therapeutic agents include viral vectorssuch as adenoviruses, gutted adenoviruses, adeno-associated virus,retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses,herpes simplex virus, replication competent viruses (e.g., ONYX-015) andhybrid vectors; and non-viral vectors such as artificial chromosomes andmini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers(e.g., polyethyleneimine, polyethyleneimine (PEI)), graft copolymers(e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP,SP1017 (SUPRATEK), lipids such as cationic lipids, liposomes,lipoplexes, nanoparticles, or microparticles, with and without targetingsequences such as the protein transduction domain (PTD).

Cells for use in conjunction with the present invention include cells ofhuman origin (autologous or allogeneic), including whole bone marrow,bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytesor macrophage, or from an animal, bacterial or fungal source(xenogeneic), which can be genetically engineered, if desired, todeliver proteins of interest.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis. Such agents areuseful for the practice of the present invention and include one or moreof the following: (a) Ca-channel blockers including benzothiazapinessuch as diltiazem and clentiazem, dihydropyridines such as nifedipine,amlodipine and nicardapine, and phenylalkylamines such as verapamil, (b)serotonin pathway modulators including: 5-HT antagonists such asketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such asfluoxetine, (c) cyclic nucleotide pathway agents includingphosphodiesterase inhibitors such as cilostazole and dipyridamole,adenylate/Guanylate cyclase stimulants such as forskolin, as well asadenosine analogs, (d) catecholamine modulators including a-antagonistssuch as prazosin and bunazosine, β-antagonists such as propranolol andα/β-antagonists such as labetalol and carvedilol, (e) endothelinreceptor antagonists, (f) nitric oxide donors/releasing moleculesincluding organic nitrates/nitrites such as nitroglycerin, isosorbidedinitrate and amyl nitrite, inorganic nitroso compounds such as sodiumnitroprusside, sydnonimines such as molsidomine and linsidomine,nonoates such as diazenium diolates and NO adducts of alkanediamines,5-nitroso compounds including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers), as well asC-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds andL-arginine, (g) Angiotensin Converting Enzyme (ACE) inhibitors such ascilazapril, fosinopril and enalapril, (h) ATII-receptor antagonists suchas saralasin and losartin, (i) platelet adhesion inhibitors such asalbumin and polyethylene oxide, (j) platelet aggregation inhibitorsincluding cilostazole, aspirin and thienopyridine (ticlopidine,clopidogrel) and GP IIb/IIIa inhibitors such as abciximab, epitifibatideand tirofiban, (k) coagulation pathway modulators including heparinoidssuch as heparin, low molecular weight heparin, dextran sulfate andβ-cyclodextrin tetradecasulfate, thrombin inhibitors such as hirudin,hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone) and argatroban,FXa inhibitors such as antistatin and TAP (tick anticoagulant peptide),Vitamin K inhibitors such as warfarin, as well as activated protein C,(l) cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,flurbiprofen, indomethacin and sulfinpyrazone, (m) natural and syntheticcorticosteroids such as dexamethasone, prednisolone, methprednisoloneand hydrocortisone, (n) lipoxygenase pathway inhibitors such asnordihydroguairetic acid and caffeic acid, (o) leukotriene receptorantagonists, (p) antagonists of E- and P-selectins, (q) inhibitors ofVCAM-1 and ICAM-1 interactions, (r) prostaglandins and analogs thereofincluding prostaglandins such as PGE1 and PGI2 and prostacyclin analogssuch as ciprostene, epoprostenol, carbacyclin, iloprost and beraprost,(s) macrophage activation preventers including bisphosphonates, (t)HMG-CoA reductase inhibitors such as lovastatin, pravastatin,fluvastatin, simvastatin and cerivastatin, (u) fish oils andomega-3-fatty acids, (v) free-radical scavengers/antioxidants such asprobucol, vitamins C and E, ebselen, trans-retinoic acid and SOD mimics,(w) agents affecting various growth factors including FGF pathway agentssuch as bFGF antibodies and chimeric fusion proteins, PDGF receptorantagonists such as trapidil, IGF pathway agents including somatostatinanalogs such as angiopeptin and ocreotide, TGF-β pathway agents such aspolyanionic agents (heparin, fucoidin), decorin, and TGF-β antibodies,EGF pathway agents such as EGF antibodies, receptor antagonists andchimeric fusion proteins, TNF-α pathway agents such as thalidomide andanalogs thereof, Thromboxane A2 (TXA2) pathway modulators such assulotroban, vapiprost, dazoxiben and ridogrel, as well as proteintyrosine kinase inhibitors such as tyrphostin, genistein and quinoxalinederivatives, (x) MMP pathway inhibitors such as marimastat, ilomastatand metastat, (y) cell motility inhibitors such as cytochalasin B, (z)antiproliferative/antineoplastic agents including antimetabolites suchas purine analogs (e.g., 6-mercaptopurine or cladribine, which is achlorinated purine nucleoside analog), pyrimidine analogs (e.g.,cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards,alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,doxorubicin), nitrosoureas, cisplatin, agents affecting microtubuledynamics (e.g., vinblastine, vincristine, colchicine, Epo D, paclitaxeland epothilone), caspase activators, proteasome inhibitors, angiogenesisinhibitors (e.g., endostatin, angiostatin and squalamine), rapamycin(sirolimus) and its analogs (e.g., everolimus, tacrolimus, zotarolimus,etc.), cerivastatin, flavopiridol and suramin, (aa) matrixdeposition/organization pathway inhibitors such as halofuginone or otherquinazolinone derivatives and tranilast, (bb) endothelializationfacilitators such as VEGF and RGD peptide, and (cc) blood rheologymodulators such as pentoxifylline.

Further additional therapeutic agents useful for the practice of thepresent invention are also disclosed in U.S. Pat. No. 5,733,925 assignedto NeoRx Corporation, the entire disclosure of which is incorporated byreference.

Numerous techniques are available for forming polymeric layers inaccordance with the present invention including, for example, solventspraying techniques, spin coating techniques, web coating techniques,dipping techniques, techniques involving coating via mechanicalsuspension including air suspension, ink jet techniques, electrostatictechniques, and combinations of these processes, among others.

For example, in some embodiments, a stationary or rotating medicaldevice substrate is spray coated. Coating application rates can varywidely, for example, ranging from 0.1-100 μg/min.

If it is desired to provide one or more therapeutic agents (and/or anyother optional agents) within the polymeric layer, so long as theseagents are stable under processing conditions, then they may be providedwithin the solution and co-processed along with the polymer(s).Alternatively, therapeutic and/or other optional agents may beintroduced subsequent to the formation of the polymeric layer in someembodiments. For instance, in some embodiments, the therapeutic and/orother optional agents are dissolved or dispersed within a solvent, andthe resulting solution contacted (e.g., using one or more of theapplication techniques described above, such as dipping, spraying, etc.)with a polymer layer.

Several specific embodiments of the invention will now be described withrespect to the formation of a polymeric layer based on a copolymer thatcontains first and second monomers, such as SIBS, SMA or PLG, among manyothers.

With such copolymers, one of the monomers will commonly be associatedwith greater adhesion to a given substrate relative to the other. Thismay be determined, for example, by analyzing homopolymers of each of themonomers. For example, a layer of each of the homopolymers may be formedon the substrate of interest, followed by evaluation of the adhesion ofeach. Adhesion may be evaluated by tests such as peel tests, frictiontests, tack tests, sonication and/or chemical resistance. Examples ofASTM standards include D3330 (15.09)(peel adhesion), D1894-01 (staticand kinetic coefficient of friction for plastic films and sheets),D1623-78, D952-02 (or similar), and A754M-96. In a preferred technique,ASTM D3330 (15.09) is used, with a slight difference in that theadhesion is not of a tape, but rather is of a polymer to a metalinterface. Testing may be performed on both dry and wet (after immersionin an aqueous solution) samples, with the latter being employed to givean indication of adhesion behavior in vivo. In this regard, in aninitial evaluation step, a fluid may be allowed to soak or flow over thepolymer coating for a given amount of time, to qualitatively observe ifthe adhesion breaks down at the polymer-metal interface.

Assuming that greater adhesion is associated with the second monomer,one can then employ a solvent that has greater affinity for the firstmonomer relative to the second monomer. Without wishing to be bound bytheory, it is believed that in selecting a solvent that has enhancedaffinity for the first monomer will concentrate the second monomer(which is associated with greater adhesion) at the interface between thesolution and the external environment, which in this instance includesthe interface with the substrate. Adhesion is improved as a result.

For example, in SIBS, greater adhesion is associated with theisobutylene (which is rubbery and tacky in homopolymer form) than withthe styrene (which is glassy and non-tacky in homopolymer form). Byproviding a solvent which has greater affinity for the polystyreneblocks, the polyisobutylene blocks are urged to the surface, making thesurface tackier and thus providing better adhesion.

One way of selecting a solvent composition that has greater affinity forthe first monomer relative to the second monomer is to select a solventwhose polarity more closely matches the polarity of the first monomerthan the second monomer. For example, a solvent can be selected whosepolarity more closely matches the polarity of a homopolymer of the firstmonomer than it does the polarity of a homopolymer of the secondmonomer.

One measure of the polarity of solvents is known as the Snyder PolarityIndex (PI). See Snyder, L. J., “Classification of the Solvent Propertiesof Common Liquids,” Chromatography, 92, 1974, 223-230. In the specificcase of a paclitaxel-containing SIBS coating, the relevant polaritiesinclude those of polystyrene, polyisobutylene, and paclitaxel. Solventcandidates that may selectively uptake each of these entities are asfollows: (a) solvents with PI ranging from about 1.8 to 3.0 (candidatesfor polystyrene uptake), solvents with PI ranging from about 2.9 to 3.7(candidates for polystyrene uptake), and solvents with PI ranging fromabout 3.9 to 4.4 (candidates for paclitaxel uptake). Examples ofsolvents for use with the paclitaxel/SIBS system, as well as variousother drug/polymer systems, may be selected from suitable members ofthose listed in paragraph [0052] of U.S. Pat. App. No. 2003/0203000 toSchwarz, among others. One of ordinary skill in the art can readilyexperiment with various solvents, including various pure solvents andsolvent mixtures, to determine suitable solvent compositions for use inthe present invention.

In general, the overall affinity of the solvent for the copolymer issuch that the solvent is able to dissolve the copolymer inconcentrations sufficient to create a solution suitable for forming apolymeric coating layer. Of course, there are limits to the amount ofsolute that can be dissolved in any given solvent (i.e., there is apoint where precipitates will begin to form in the solution).

Another method for selecting a solvent composition that has greateraffinity for one monomer over another is to find a solvent in which thefirst monomer is more soluble than the second monomer. For example, asolvent can be selected in which a homopolymer of the first monomer hasa solubility that is significantly greater (e.g., 2 to 5 to 10 or moretimes) than that of a homopolymer of the second monomer. Although not arequirement, homopolymers may be of similar molecular weight for theevaluation. Moreover, if a block polymer is being evaluated, solubilitymay be determined for homopolymers whose molecular weights are similarto those of the polymer blocks within the block copolymer. As above, theoverall affinity of the solvent for the copolymer is generally such thatthe solvent is able to dissolve the copolymer in suitableconcentrations.

Again without wishing to be bound by theory, it is believed thatselecting a solvent which has enhanced affinity for the first monomerresults in higher surface concentrations of the second monomer at theinterface with the substrate. In the case of SIBS, by providing asolvent which has greater affinity for polystyrene blocks, thepolyisobutylene blocks are urged to the surface, increasing the surfacetack and thus providing better adhesion.

Surface concentration may be measured/characterized, for example, byatomic force microscopy (AFM) or X-ray Photoelectron Spectroscopy (XPS),among other techniques.

While the initial solution composition may be selected to provide goodadhesion at the substrate interface, the same solution may not provideoptimized properties elsewhere within the polymeric layer, including thebulk and/or opposite interface (top surface) of the layer. (For example,in the case of block copolymer, a change in solvent composition willtypically result in a change in the way that the phase domains arearranged in the bulk and at the top surface, affecting the properties ofthese regions.) The solution composition is therefore changed as thelayer is deposited to optimize such properties.

Returning again to the example of SIBS, as noted above, adhesion may beimproved by choosing a solvent in which uptake of the polystyrenemonomer is preferred over the isobutylene, resulting in a higher surfaceconcentration of isobutylene monomer (e.g., in the form of phase domainsformed from the polyisobutylene blocks), which leads to greater surfacetack. Such surface tack, however, may not be desirable at the outersurface of the stent, because properties associated with the coatingsurface may lead to issues with the delivery and/or use of the product.

Moreover, in instances where polymeric layers act as drug deliveryreservoirs, it has been found that solution composition influences thekinetic drug release (KDR) from the same. Frequently, a solutioncomposition which optimizes adhesion will not be the same as a solutioncomposition for which drug release has been optimized.

In the case of SIBS, and as noted above, a solvent composed of a mixtureof toluene and THF is not particularly beneficial from an adhesionstandpoint. It may therefore be desirable, for example, to initiallyapply to the substrate a SIBS solution that contains another solventcomposition so as to improve surface adhesion. Once the surface of thesubstrate is covered with SIBS, the solvent system may be changed, forexample, to provide a desired KDR. For example, one could employ amixture of toluene and THF as a solvent in forming the remainder of thelayer, which combination has been demonstrated to release paclitaxelwith a KDR that is safe and effective for the treatment of restenosis.In some embodiments, paclitaxel is not included in the initial solution,but is introduced as the solvent is modified.

In some embodiments, the initial solution may be applied until a layerthickness ranging from 0.1 to 0.5 to 1 to 5 μm is established, with thelayer continuing to be built up after the solvent change to a thicknessranging from 0.2 to 0.5 to 1 to 5 to 25 to 50 μm.

In some embodiments, there is an abrupt transition in solutioncomposition forming the layer. In others, there is a gradual change insolution composition, leading to a gradient in properties as oneproceeds from the lower interface with the substrate to the upperinterface.

In addition to the polymer, drug and solvent species that are selectedand their relative amounts (which, in addition to affecting variousproperties of the polymeric layer as previously above, also affectvarious solution properties, including solution viscosity, surfacetension, drying rate, etc.), the coating process is also typicallyoptimized, for example, with respect to substrate surface energy (whichaffects the wettability of substrate), the coating technique employed(e.g., spray, print, roll, dip, etc), curing/drying conditions, and soforth.

In many of the above embodiments of the invention, the properties of thepolymeric layer are optimized by changing the solution concentration. Infurther embodiments, the properties are optimized by varying the polymercomposition of the polymeric solution. For example, an initial solutionhaving a first polymer composition may be applied until a layerthickness ranging from 0.1 to 0.5 to 1 to 5 μm is established, with thelayer continuing to be built up after a polymer composition change to athickness ranging from 0.2 to 0.5 to 1 to 5 to 25 to 50 μm. As above,the composition change may be gradual or abrupt (stepwise).

For example, where a copolymer comprising first and second monomers isemployed and where the second monomer provides enhanced adhesionrelative to the first monomer, the ratio of the second monomer may behigher in the early stages of layer formation, relative to the latterstages. For instance, in the case of SIBS, the ratio of isobutylene tostyrene may be decreased from a mole ratio of, for example, 7 to 10 to15 to 20 or higher to a molar ratio of 5.25, which has been demonstratedto release paclitaxel with a KDR that is safe and effective for thetreatment of restenosis.

As another example, the molecular weight of the coating polymer(s) maybe changed as a function of coating depth. For example, the molecularweight(s) of the coating polymer(s) may be changed as one approaches thesurface to either increase or decrease surface hardness, among otherpossibilities.

In embodiments where a blend of polymers is employed within the polymerlayer, adhesion may be optimized by varying the ratio of one polymerrelative to another within the polymeric solution as a function ofcoating depth. For example, where a second polymer provides enhancedadhesion relative to a first monomer, the ratio of the second polymer tothe first polymer may be higher in the initial stages of layerformation, relative to the latter stages.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

1-21. (canceled)
 22. A medical device comprising a substrate and apolymeric layer that comprises a copolymer disposed over the substrate,the copolymer comprising differing first and second monomers, wherein afirst homopolymer of the first monomer adheres to the substrate betterthan a second homopolymer the second monomer, and wherein the lowersurface of the polymeric layer contacting the substrate has a highersurface concentration of the first monomer relative to the secondmonomer than does the upper surface of the polymeric layer opposite thesubstrate.
 23. The medical device of claim 22, wherein the upper surfaceof the polymeric layer has a higher surface concentration of the secondmonomer relative to the first monomer.
 24. The medical device of claim22, wherein the first monomer is isobutylene and the second monomer isstyrene.
 25. The medical device of claim 22, wherein the copolymer is ablock copolymer comprising a first polymer block comprising the firstmonomer and a second polymer block comprising the second monomer. 26.The medical device of claim 25, wherein the first monomer is isobutyleneand the second monomer is styrene.
 27. The medical device of claim 22,wherein the substrate is a metallic substrate.
 28. The medical device ofclaim 22, wherein the medical device is selected from a stent, a filter,a lead for a cardiac rhythm management (CRM) device, a sensor, a valveand an aneurism filler coil.
 29. The medical device of claim 22, whereinthe medical device is a stent.
 30. The medical device of claim 22,wherein the layer further comprises a therapeutic agent.
 31. The medicaldevice of claim 30, wherein the therapeutic agent is selected fromanti-thrombotic agents, anti-proliferative agents, anti-inflammatoryagents, anti-migratory agents, agents affecting extracellular matrixproduction and organization, antineoplastic agents, anti-mitotic agents,anesthetic agents, anti-coagulants, vascular cell growth promoters,vascular cell growth inhibitors, cholesterol-lowering agents,vasodilating agents, agents that interfere with endogenous vasoactivemechanisms, and combinations thereof.
 32. The medical device of claim23, wherein the substrate is a metallic substrate.
 33. The medicaldevice of claim 23, wherein the medical device is selected from a stent,a filter, a lead for a cardiac rhythm management (CRM) device, a sensor,a valve and an aneurism filler coil.
 34. The medical device of claim 23,wherein the medical device is a stent.
 35. The medical device of claim23, wherein the layer further comprises a therapeutic agent.
 36. Themedical device of claim 35, wherein the therapeutic agent is selectedfrom anti-thrombotic agents, anti-proliferative agents,anti-inflammatory agents, anti-migratory agents, agents affectingextracellular matrix production and organization, antineoplastic agents,anti-mitotic agents, anesthetic agents, anti-coagulants, vascular cellgrowth promoters, vascular cell growth inhibitors, cholesterol-loweringagents, vasodilating agents, agents that interfere with endogenousvasoactive mechanisms, and combinations thereof.
 37. The medical deviceof claim 25, wherein the substrate is a metallic substrate.
 38. Themedical device of claim 25, wherein the medical device is selected froma stent, a filter, a lead for a cardiac rhythm management (CRM) device,a sensor, a valve and an aneurism filler coil.
 39. The medical device ofclaim 25, wherein the medical device is a stent.
 40. The medical deviceof claim 25, wherein the layer further comprises a therapeutic agent.41. The medical device of claim 40, wherein the therapeutic agent isselected from anti-thrombotic agents, anti-proliferative agents,anti-inflammatory agents, anti-migratory agents, agents affectingextracellular matrix production and organization, antineoplastic agents,anti-mitotic agents, anesthetic agents, anti-coagulants, vascular cellgrowth promoters, vascular cell growth inhibitors, cholesterol-loweringagents, vasodilating agents, agents that interfere with endogenousvasoactive mechanisms, and combinations thereof.